Iron -overload regulatory effect on cytokine production by spleen lymphocytes in munine cryptosporidiosis the modulatoncy potential potential of iron chelation therapy on immunity

ABSTRACT

Iron-overload both aggravates the outcome of infections caused by a variety of microorganisms and exerts subtle effects on immune status by altering the proliferation of T and B cells. The effect of iron-overload on the type of T helper [Th] immunity elicited and the subsequent effect on the susceptibility, course and outcome of Cryptosporidium parvum infection were investigated in the present study. Separate groups of iron-overloaded [40 mg of iron dextran/kg intraperitoneally every other day for 4 weeks before infection] immunocompetent and immunocompromised mice were either infected or infected and received iron chelator [deferoxanime DFO. 50 mg/kg intraperitoneally every other day from the day of infection]. Spleens were harvested and an enzyme linked immunosorbent assay [ELISA] was performed on spleen culture supernatants for in vitro analysis of interferon-gamma [IFN-gamma] and interleukin [IL]-4. Iron-overload induced a Th2 cytokine response with significantly higher IL-4 and lower IFN-gamma levels compared to infected non- treated control. The infection rate was 100% and the infection was severe and persistent in both immunocompetent and immunocompromised iron-overloaded mice with death of all immunocompromised mice. Iron chelation by DFO enhanced the production of Th1 anticryptosporidial immunity [significantly higher IFN-gamma compared to infected non- treated control] limiting the severity and clearing the infection in iron-overloaded immunocompetent mice [cure rate 100%] and controlling the infection in immunocompromised mice with cure rate 30%, percentage reduction in oocyst shedding 80.8% and mortality rate 10% at the end of the experiment [30 days post infection]. These data indicated that iron-overload negatively affected Th1-mediated immunity in mice with cryptosporidiosis thus altering the susceptibility, course and outcome of infection. Iron-overload represents a risk factor for flaring up of Cryptosporidium parvum infection in absence of any obvious immunosuppressive conditions; hence successful therapy in iron-overloaded hosts depends mainly on iron chelation. The immunomodulatory properties of DFO were elucidated in terms of restoring Th1 immunity in iron-overloaded mice